rs2303191

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016373.4(WWOX):c.516+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 1,612,444 control chromosomes in the GnomAD database, including 433,805 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 43510 hom., cov: 31)

Exomes 𝑓: 0.73 ( 390295 hom. )

Consequence

WWOX
NM_016373.4 splice_region, intron

Scores

Splicing: ADA: 0.0002358

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.92

Publications

12 publications found

Variant links:

Genes affected

WWOX (HGNC:12799): (WW domain containing oxidoreductase) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

WWOX Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive spinocerebellar ataxia 12
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
developmental and epileptic encephalopathy, 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
46,XY partial gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WWOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 16-78164295-T-C is Benign according to our data. Variant chr16-78164295-T-C is described in ClinVar as Benign. ClinVar VariationId is 260739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.516+6T>C	splice_region_variant, intron_variant	Intron 5 of 8	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7
WWOX	NM_001291997.2 link	c.177+6T>C	splice_region_variant, intron_variant	Intron 4 of 7		NP_001278926.1	Q9NZC7
WWOX	NM_130791.5 link	c.516+6T>C	splice_region_variant, intron_variant	Intron 5 of 5		NP_570607.1	Q9NZC7-3
WWOX	NR_120436.3 link	n.755+6T>C	splice_region_variant, intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 link	c.516+6T>C		splice_region_variant, intron_variant	Intron 5 of 8	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.754

AC:

114579

AN:

151990

Hom.:

43457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.799

Gnomad AMI

AF:

0.632

Gnomad AMR

AF:

0.791

Gnomad ASJ

AF:

0.677

Gnomad EAS

AF:

0.905

Gnomad SAS

AF:

0.745

Gnomad FIN

AF:

0.703

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.722

Gnomad OTH

AF:

0.741

GnomAD2 exomes

AF:

0.748

AC:

185664

AN:

248274

AF XY:

0.741

show subpopulations

Gnomad AFR exome

AF:

0.800

Gnomad AMR exome

AF:

0.827

Gnomad ASJ exome

AF:

0.686

Gnomad EAS exome

AF:

0.890

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.717

Gnomad OTH exome

AF:

0.723

GnomAD4 exome

AF:

0.730

AC:

1065815

AN:

1460336

Hom.:

390295

Cov.:

AF XY:

0.728

AC XY:

528886

AN XY:

726428

show subpopulations

African (AFR)

AF:

0.803

AC:

26870

AN:

33460

American (AMR)

AF:

0.822

AC:

36716

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.679

AC:

17734

AN:

26112

East Asian (EAS)

AF:

0.906

AC:

35954

AN:

39684

South Asian (SAS)

AF:

0.724

AC:

62354

AN:

86068

European-Finnish (FIN)

AF:

0.694

AC:

37003

AN:

53356

Middle Eastern (MID)

AF:

0.633

AC:

3645

AN:

5762

European-Non Finnish (NFE)

AF:

0.721

AC:

801489

AN:

1110900

Other (OTH)

AF:

0.730

AC:

44050

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

14068

28137

42205

56274

70342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20024

40048

60072

80096

100120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.754

AC:

114691

AN:

152108

Hom.:

43510

Cov.:

AF XY:

0.753

AC XY:

55990

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.799

AC:

33141

AN:

41492

American (AMR)

AF:

0.792

AC:

12087

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.677

AC:

2350

AN:

3472

East Asian (EAS)

AF:

0.905

AC:

4673

AN:

5164

South Asian (SAS)

AF:

0.745

AC:

3590

AN:

4820

European-Finnish (FIN)

AF:

0.703

AC:

7437

AN:

10582

Middle Eastern (MID)

AF:

0.622

AC:

183

AN:

294

European-Non Finnish (NFE)

AF:

0.722

AC:

49085

AN:

67996

Other (OTH)

AF:

0.744

AC:

1571

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1464

2928

4391

5855

7319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.731

Hom.:

17803

Bravo

AF:

0.764

Asia WGS

AF:

0.838

AC:

2915

AN:

3478

EpiCase

AF:

0.713

EpiControl

AF:

0.720

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 97% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 90. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 28

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive spinocerebellar ataxia 12

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.2

(source)

DANN

Benign

0.48

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00024

dbscSNV1_RF

Benign

0.046

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over